Metabolic-dysfunction associated steatotic liver disease and atrial fibrillation: A review of pathogenesis

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) significantly contributes to cardiovascular morbidity, with cardiovascular disease being the leading cause of mortality among affected individuals. Atrial fibrillation (AF), the most common cardiac arrhythmia, is frequently observed in patients with MASLD. While shared metabolic risk factors such as obesity, diabetes, dyslipidemia, and hypertension are implicated, underlying pathophysiological mechanisms that include systemic inflammation, oxidative stress, insulin resistance, endothelial dysfunction, and activation of the renin-angiotensin-aldosterone system (RAAS) are proposed to play significant part in the increased risk of AF in MASLD. The aim is to review the pathogenesis linking MASLD and AF. A comprehensive literature review was conducted, focusing on studies that explore the epidemiology, pathogenesis, and clinical implications of MASLD and AF. Databases searched included PubMed, Scopus, and Web of Science, with keywords such as “metabolic associated steatotic liver disease”, “non fibrotic metabolic associated steatohepatitis”, “Nonalcoholic fatty liver disease”, “metabolic syndrome”, “atrial fibrillation”, “antifibrotic therapies”, "pathogenesis", and "cardiovascular risk". Chronic low-grade inflammation and oxidative stress in MASLD contribute to atrial structural and electrical remodeling, fostering an arrhythmogenic substrate. Insulin resistance, a hallmark of MASLD, exacerbates metabolic dysfunction and promotes atrial fibrosis. Dysregulated lipid metabolism and gut microbiota alterations further compound cardiovascular risk. Aldosterone dysregulation and systemic inflammation stemming from RAAS activation contributes to the shared pathophysiology. The severity of MASLD does not seem to directly influence the risk of AF, suggesting that even early stages of liver disease can increase susceptibility to this arrhythmia. Effective management of MASLD requires targeted risk-factor modification strategies, including weight management, glycemic control, and pharmacological interventions. A multidisciplinary approach is essential for comprehensive assessment and management of MASLD patients, with a focus on cardiovascular risk assessment and arrhythmia prevention. Future research should explore the impact of emerging MASLD therapeutic agents on the incidence and recurrence of cardiac arrhythmias. Early detection and comprehensive management of MASLD and AF are crucial to mitigate the dual burden of these conditions.

Key Words: Metabolic-dysfunction associated steatotic liver disease; Non-alcoholic fatty liver disease; Atrial fibrillation; Non-alcoholic steatohepatitis; Insulin resistance; Oxidative stress; Dyslipidemia; Obesity

Core Tip: Metabolic dysfunction-associated steatotic liver disease (MASLD) and atrial fibrillation (AF) share common metabolic risk factors, including obesity, diabetes, dyslipidemia, and hypertension. Pathophysiological mechanisms such as systemic inflammation, oxidative stress, insulin resistance, and renin-angiotensin-aldosterone system activation link MASLD to AF. Chronic inflammation and oxidative stress in MASLD lead to atrial remodeling, creating an arrhythmogenic substrate. Effective management of MASLD requires targeted risk-factor modification strategies and a multidisciplinary approach to reduce cardiovascular risk and prevent arrhythmias. Early detection and comprehensive management are crucial to mitigate the dual burden of MASLD and AF.

INTRODUCTION

Metabolic associated steatotic liver disease (MASLD) is increasingly recognized as a significant risk factor for various cardiovascular conditions, particularly atrial fibrillation (AF)[1]. MASLD is the most common liver disease in the United States, affecting approximately 30% of the population, with a higher prevalence among diabetics[2]. Characterized by the accumulation of fat in the liver due to metabolic dysfunctions such as insulin resistance (IR) and chronic low-grade inflammation, MASLD is associated with a heightened risk of cardiovascular complications, including AF, which affects millions worldwide[3]. Due to common modifiable risk factors such as hypertension, diabetes, and obesity between AF and MASLD, researchers have been investigating the association that exists between these two heterogeneous conditions.

In recent years, the nomenclature surrounding fatty liver disease has undergone a significant transformation[4]. In 2020, hepatology experts acknowledged the need to update the terminology for non-alcoholic fatty liver disease (NAFLD) to better reflect its metabolic origins. The renaming of nonalcoholic steatohepatitis to metabolic dysfunction-associated steatohepatitis as well as NAFLD to MASLD signifies emphasis toward metabolic causes of liver disease, aiming to eliminate the stigma associated with "non-alcoholic" and highlight the metabolic dysfunction underlying the condition[4]. This shift was further solidified in June 2023 with the publication of a multi-society Delphi consensus statement, which formally retired the term NAFLD and introduced a more comprehensive classification system. While MASLD remains a broad category, MASH represents a more severe form, characterized by inflammation, liver damage, and an increased risk of fibrosis, cirrhosis, and liver cancer. This reclassification represents an effort to refine disease definitions to enhance patient care, improve diagnostic criteria, and streamline research efforts[4].

While some studies have reported an association[1,5], other studies in contrast have reported that liver stiffness and not steatosis is a risk factor for the development of AF[6]. Research highlights a significant link, showing that people with MASLD face a 19% higher likelihood of developing AF compared to those without the condition, with this risk increasing in individuals with more advanced liver disease[1,5] (Table 1). The underlying mechanisms linking MASLD and AF are complex, involving metabolic dysregulation, dyslipidemia, and endothelial dysfunction. Elevated pro-inflammatory cytokines contribute to systemic inflammation and vascular complications, promoting a pro-atherogenic state that can precipitate arrhythmias. Furthermore, hypertension, often exacerbated by MASLD, may serve as an additional pathway linking the two conditions[7-12]. AF, the most prevalent type of arrhythmia, often serves as the ultimate pathway for numerous underlying cardiac and non-cardiac conditions. If not addressed, it can result in severe health complications such as stroke and heart failure[13]. Given the rising prevalence of both MASLD and AF, cardiovascular disease (CVD) being the leading cause of mortality in patients with MASLD and the healthcare burden associated with AF continuing to rise, understanding the interplay between MASLD and AF becomes crucial for public health initiatives and clinical practice[14,15]. This review examines the current literature, proposed pathogenetic mechanisms, and treatment implications for patients with MASLD and AF.

Table 1 Summary of key studies that highlight the increased risk of atrial fibrillation in patients with metabolic-associated steatotic liver disease, non-alcoholic fatty liver disease, and metabolic-associated steatohepatitis.

Study	Ref.	Year	Type	Population	Key findings
Incident cardiac arrhythmias associated with MASLD	Simon et al[18]	2023	Retrospective cohort	11206 Swedish adults with histologically-confirmed MASLD	MASLD patients had a significantly higher incidence of AF (aHR = 1.26, 95%CI: 1.18-1.35) compared to controls
MASLD is associated with an increased long-term risk of AF	Mantovani et al[21]	2024	Systematic review and meta-analysis	16 retrospective cohort studies with approximately 19.5 million individuals	MASLD is associated with an increased risk of developing AF
Cardiovascular disease and MASLD	Møller et al[20]	2025	Systematic review	General review of MASLD patients	MASLD is associated with increased risk of cardiovascular diseases, including AF
Non-alcoholic fatty liver disease and the risk of incident AF in young adults	Choi et al[23]	2022	Prospective cohort	5333907 young adults in South Korea	NAFLD patients had a higher risk of new-onset AF, which increased progressively with NAFLD severity
Association of NAFLD with new-onset AF stratified by age groups	Cho et al[1]	2024	Retrospective cohort	3179582 participants from the Korean National Health Screening Program	NAFLD patients had a higher risk of new-onset AF, which increased progressively with NAFLD severity

AF: Atrial fibrillation; MASLD: Metabolic dysfunction-associated steatotic liver disease; NAFLD: Non-alcoholic fatty liver disease; aHR: Adjusted hazard ratio.

EPIDEMIOLOGY

AF is the most prevalent cardiac arrhythmia worldwide, posing a significant public health challenge. Recent studies estimate that 10.55 million American adults, or 4.48% of the United States population, are currently affected by AF[16]. These figures represent a staggering threefold rise compared to projections from the 1990s, underscoring the rapid rise in disease burden. AF affects approximately 37.6 million individuals globally, accounting for 0.51% of the global population. Alarmingly, the absolute burden of AF is expected to grow by more than 60% by 2050, driven by aging populations and the increasing prevalence of associated comorbidities[16]. Age remains a dominant risk factor for AF, with a lifetime incidence of approximately 33% in individuals aged 65 years and older[17]. However, age-related susceptibility is often compounded by metabolic and cardiovascular comorbidities, including obesity, diabetes, hypertension, and, most notably, MASLD. Emerging evidence highlights MASLD as a significant contributor to AF, by some estimates increasing the risk by 19%, mediated through shared risk factors and overlapping pathophysiologic mechanisms[18].

MASLD is a chronic condition the hallmark of which is fat deposition in the liver. It affects an estimated 80-100 million individuals in the United States alone and has a global prevalence that mirrors rising rates of obesity and metabolic syndrome[19]. Studies have reported MASLD prevalence among obese individuals in the United States approaches 75%, reflecting the interconnected nature of these conditions[19]. Several studies have established an epidemiological link between MASLD and AF[20-23]. A meta-analysis has demonstrated that patients with MASLD have a 19% greater risk of developing incident AF compared to those without MASLD, as indicated by an adjusted hazard ratio (aHR) of 1.19 (95%CI: 1.07-1.31)[18]. Furthermore, the association between MASLD and AF persists across various histological categories of liver disease. Patients diagnosed with simple steatosis have an aHR of 1.24 (95%CI: 1.14-1.35). In contrast, those suffering from non-fibrotic MASH and cirrhosis face even higher risks, with aHRs of 1.34 (95%CI: 1.07-1.68) and 1.59 (95%CI: 1.15-2.19), respectively[18]. This finding underscores the importance of fibrosis progression as a key determinant of arrhythmogenic risk in MASLD. Another study involving 238129 participants further corroborated these findings, showing that MASLD patients had a twofold increased risk of AF compared to those without the condition[15]. These studies highlight the interplay between liver disease severity and cardiac arrhythmogenesis, suggesting that MASLD progression may independently elevate AF risk, even when accounting for traditional cardiometabolic risk factors.

Both AF and MASLD share common risk factors, including obesity, diabetes, hypertension, and dyslipidemia, complicating efforts to delineate their causal relationship[20-24]. Obesity, a central driver of metabolic dysfunction, plays a particularly critical role[25]. Visceral fat accumulation is associated with IR, systemic inflammation, and hormonal imbalances, all of which contribute to both hepatic steatosis and atrial remodeling[25]. Up to 75% of obese individuals in the United States have MASLD, highlighting the high prevalence of this liver disease in populations at risk for AF[19]. Obesity significantly increases the likelihood of hepatic steatosis[26]. Patients meeting the criteria for metabolic syndrome demonstrate a notably higher risk of steatohepatitis and severe fibrosis. The growing obesity epidemic has thus driven parallel increases in the prevalence of both MASLD and AF, particularly in Western countries and parts of Asia[26]. A recent meta-analysis to assess a study on the global impact of obesity across 73 World Health Organization member countries found that 37% of individuals were affected by overweight or obesity issues[27]. The research also indicated that nations with a strong economic standing tend to have a higher rate of overweight and obesity. In fact, an improvement in economic status could result in a 14% rise in these conditions[27].

MASLD and AF are interconnected public health challenges. While strong epidemiological and mechanistic evidence links these conditions, distinguishing the direct impact of MASLD on the risk of AF in the presence of overlapping factors remains challenging. As the evidence continues to accumulate, the need for targeted screening and interventions for MASLD patients at elevated risk of developing AF becomes increasingly clear, particularly as cardiovascular mortality has surpassed liver-related deaths in this patient group[24].

PATHOGENESIS

AF is a complex condition that can present as an isolated electrophysiological disorder or as a consequence of various cardiac and non-cardiac pathologies. The pathophysiological mechanisms that connect MASLD to an elevated risk of AF are intricate and encompass various processes, which will be elaborated upon in the subsequent sections.

SHARED RISK FACTORS

IR and diabetes mellitus

IR is a metabolic disorder characterized by the body's diminished ability to respond to insulin, leading to impaired glucose metabolism and elevated blood glucose levels. This condition serves as a significant precursor to various metabolic disorders, including type 2 diabetes and metabolic syndrome[28]. IR also affects vessels, leading to hypertension and vasoconstriction[29]. IR is increasingly being linked to the pathogenesis of AF and MASLD, highlighting its pivotal role in the development of these conditions.

IR is a central feature of the onset of MASLD, affecting lipid metabolism and contributing to various metabolic disorders. IR disrupts the conversion of free fatty acids (FFAs) into triglycerides (TGs) and their incorporation into very low-density lipoprotein particles for storage or transport, resulting in fat buildup in liver cells and worsening hepatic steatosis[30] (Figure 1A). On a molecular level, the dysregulation of essential transcription factors, such as sterol regulatory element-binding protein 1c (SREBP1c) and carbohydrate regulatory element-binding protein, drives IR in MASLD. These factors regulate the expression of genes involved in lipogenesis and glucose metabolism[3]. Research indicates that elevated glucose levels can stimulate SREBP1c, which in turn enhances lipogenic gene expression and excess FFAs production, promoting lipid accumulation in hepatocytes which leads to hepatic steatosis or MASLD[31]. Decreased insulin action can result in decreased glycogen synthesis in skeletal muscle, increased hepatic de novo lipogenesis (DNL), and elevated TG synthesis, which collectively contribute to atherosclerotic dyslipidemia in individuals with MASLD[32].

Figure 1 Role in atrial fibrillation and metabolic dysfunction-associated steatotic liver disease. A: Insulin resistance and diabetes mellitus; B: Obesity and obstructive sleep apnea; C; Dyslipidemia; D: Hypertension; E: Proposed role of endothelial dysfunction. AF: Atrial fibrillation; AFib: Atrial fibrillation; FFA: Free fatty acid; IR: Insulin resistance; LA: Left atrium; RAAS: Renin-angiotensin-aldosterone-system; TG: Triglycerides; SREBP1c: Sterol regulatory element binding protein 1c; K: Potassium; TNF: Tumor necrosis factor-α; HDL: High desnity lipoprotein; MASLD: Metabolic dysfunction-associated steatotic liver disease; Ox-LDL: Oxidized low-density lipoprotein; SdLDL: Small-density low-density lipoprotein; ADH: Antidiuretic hormone; ADMA: Asymmetric dimethylarginine; IL: Interleukin; VEGF: Vascular endothelial growth factor; Na: Sodium. Created in BioRender (Supplementary material).

IR has emerged as a significant risk factor for AF, influencing both the pathophysiology and progression of the condition. Several molecular mechanisms contribute to the association between IR and CVD s including AF[29]. Structural remodeling of the atria and disruption of intracellular calcium homeostasis is caused by adipocyte inflammation and oxidative stress which are linked to IR[33]. The increased oxidative stress and inflammation associated with impaired IR and insulin secretion contribute to left atrial (LA) fibrosis and the formation of a low-pressure area in the LA along with left ventricular hypertrophy (LVH), all of which are critical components in the pathophysiology of AF[28,34]. IR contributes to hyperinsulinemia, which can initiate mechanisms that modify vascular compliance and matrix remodeling. These physiological alterations enhance renal sodium reabsorption and activate the sympathetic nervous system, leading to left ventricular (LV) remodeling and the development of LVH[35]. Additionally, abnormal glucose tolerance and dyslipidemia related to IR have a cumulative effect on the risk of AF progression, thereby leading to recurrence after interventions such as radiofrequency catheter ablation[28].

Diabetes mellitus has been implicated as a significant risk factor for both AF and MASLD, highlighting a complex interplay among these conditions. The association between MASLD and type 2 diabetes mellitus (T2DM) is substantial, with over 70% of individuals with T2DM exhibiting MASLD[36]. Furthermore, the presence of MASLD in diabetic patients can complicate metabolic health and increase the risk of cardiovascular events[18,37]. A meta-analysis examining the association between MASLD and AF has demonstrated a significant increase in the risk of AF among middle-aged and elderly individuals with MASLD, with the risk being particularly elevated among diabetic patients[38]. Independent from MASLD, evidence suggests Diabetes Mellitus is a significant and independent risk factor for AF and flutter, as well as other CVDs, with some estimates indicating a 1.4- to 1.6-fold increased risk of AF[39-41]. Furthermore, a prolonged period of suboptimally controlled diabetes mellitus has been independently linked to a heightened risk of AF[37,41].

Obesity and obstructive sleep apnea

Obesity, characterized by excessive fat accumulation, plays a crucial role in the development of MASLD primarily through mechanisms that promote hepatic lipid accumulation and metabolic dysregulation. In obese individuals, excessive caloric intake and physical inactivity exacerbate the accumulation of fat deposits in the liver[25]. Dietary patterns high in sugars and unhealthy fats increase DNL, leading to further fat deposition in hepatocytes[42]. Obesity is also associated with obstructive sleep apnea (OSA) along with IR, T2DM, MASLD, and other related metabolic diseases[43,44]. In fact, more severe OSA is associated with a higher prevalence of MASLD, body mass index (BMI), and oxygen desaturation index[45]. Intermittent awakening in OSA triggers the sympathetic system and hypothalamic-pituitary-adrenal axis to reduce glucose uptake, promote reactive oxygen species (ROS) generation, and trigger apoptosis of beta-cells in the pancreas[46]. The hypoxia in OSA induces TG and cholesterol ester synthesis, increased generation and decreased beta-oxidation of FFAs, and lipid mobilization from adipose to liver, predisposing patients to dyslipidemia[47,48]. This dysregulation often leads to lipotoxicity, triggering a cascade of pathophysiological changes that lead to liver damage as a consequence of oxidative stress, pro-inflammatory state, and activation of the renin-angiotensin axis and, ultimately, fibrosis[49,50]. High malondialdehyde levels have been observed in the liver as well as the serum of mice exposed to intermittent hypoxia[51]. These effects augment lipotoxicity which plays a critical role in the development and progression of MASLD. OSA impacts sleep quality and prior studies have found an association between low sleep duration and MASLD[52]. This is partly explained by the role of circadian rhythm in regulating insulin and lipid metabolism, the disturbance of which could promote inflammation and liver disease[53].

Obesity and OSA lead to systemic changes that may predispose individuals to AF (Figure 1B). In individuals with obesity, the increased cardiac output induces hemodynamic modifications that accelerate the progression of LVH and LV diastolic dysfunction[54]. LV dysfunction, along with hyper circulatory state, sleep apnea, sleep related hypoventilation and hypoxemia may result in involvement of the right heart, thereby further exacerbate alterations in cardiac morphology[55]. Moreover, the relative risk of incident AF increases by 19%-29% for each 5-unit increase in BMI above normal[56]. Furthermore, individuals with OSA exhibit a fourfold increase in the likelihood of developing AF. This elevated risk is quantified by an adjusted odds ratio, which, after adjusting for concurrent risk factors, ranges from 2.8 to 5.6[57,58]. The association of obesity and AF is two-fold, with the first pathway being through the excess adipose tissue and the second pathway involving the deposition of fat around the heart (epicardial fat). The pro-inflammatory and pro-fibrotic factors secreted by the former promote diastolic dysfunction, atrial inflammation, myocardial lipidosis, and atrial contractile dysfunction[25]. This is further complicated by intermittent nocturnal hypoxia in OSA that promotes endothelial dysfunction, hypercapnia, chemoreceptor stimulation and causes significantly elevated sympathetic activity along with severe blood pressure changes[59,60]. Furthermore, the inflammatory cytokine tumor necrosis factor-α (TNF-α) plays a pivotal role in this remodeling process by altering ion channel function characterized by a downregulation of calcium currents and increased outward potassium currents, leading to slowed conduction and shortened atrial refractory periods[61]. Collectively, these factors result in substantial alterations in cardiac chamber dimensions and transmural pressures, creating a substrate that facilitates the development and perpetuation of AF[8,62-64]. In contrast, epicardial fat, a type of ectopic adipose tissue, is metabolically active and secretes cytokines and chemokines that may contribute to the development of atrial arrhythmias[65]. Research indicates that inflammatory biomarkers, including interleukin (IL)-1β and TNF-α, may contribute to the development of atrial fibrosis by exerting paracrine effects on the surrounding myocardium. Furthermore, these biomarkers might lead to disruption of conduction wavefronts by fatty infiltration leading to the formation of micro reentry circuits[66]. OSA severity independently correlates with elevated markers of systemic inflammation, such as C-reactive protein (CRP). CRP, in turn, demonstrates a direct association with atrial remodeling and increased risk of arrhythmias including AF[67]. In addition, both hypoxemia and hypercapnia possess arrhythmogenic properties[68]. If left untreated for years, these recurring events may precipitate or increase susceptibility to AF[69,70]. In a population-based study, robust and graded correlations were identified between increased epicardial fat and AF, with the association potentially surpassing that of abdominal and overall adiposity[71]. Hence, the interplay between obesity, OSA, AF, and MASLD reveals a complex web of pathophysiological mechanisms that elevate the risk for CVDs.

Dyslipidemia

Dyslipidemia is a metabolic disorder characterized by abnormal lipid levels in the blood, and it plays a pivotal role in the pathogenesis of MASLD and AF (Figure 1C). Dyslipidemia is prevalent in approximately 60%-70% of individuals with MASLD[24]. The interplay between dyslipidemia and MASLD involves complex mechanisms, including genetic factors, impaired insulin sensitivity, and chronic inflammation[72,73]. Dyslipidemia is characterized by increased levels of TGs, the presence of small dense low-density lipoprotein cholesterol (sdLDL), and diminished high-density lipoprotein cholesterol (HDL-C) concentrations. The propensity of sdLDL to infiltrate the endothelium and undergo oxidation to form ox-LDL activates inflammatory cascades integral to atherosclerotic plaque genesis[72]. Due to their diminished affinity for LDL receptors, the reduced clearance of these particles amplifies their atherogenic potential[74]. Concomitantly, the decline in HDL levels compromises reverse cholesterol transport and attenuates HDL's antioxidant and anti-inflammatory properties, thereby impeding the breakdown of excess cholesterol[75]. This aberrant lipid profile not only aggravates liver disease but also heightens the susceptibility to cardiovascular complications, notably atherosclerosis and AF[24].

The development of dyslipidemia in MASLD can be influenced by both genetic predispositions and environmental factors. Specific genetic polymorphisms, such as the single nucleotide polymorphism (SNP) rs738409 in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, have been associated with increased liver fat accumulation and a higher risk of progressive liver disease, which may in turn affect lipid metabolism[76]. The systemic inflammation and oxidative stress associated with MASLD and dyslipidemia contribute to cardiovascular pathologies, including AF. Elevated levels of inflammatory cytokines, such as TNF-α and IL-6, are not only linked to liver inflammation but also facilitate endothelial dysfunction, which is a precursor to AF[7]. The inflammatory milieu may induce electrical remodeling in the atria, increasing the risk of arrhythmias, including AF. Furthermore, the metabolic abnormalities seen in MASLD can disrupt cardiac autonomic function, which further exacerbates the likelihood of developing AF[7,77]. Dyslipidemia’s association with AF is particularly notable yet controversial. While certain studies indicate that dyslipidemia may influence AF risk, higher levels of total cholesterol (TC) and LDL-C have been associated with a lower risk of AF in some studies, but this association appears to be time-dependent and may not persist beyond the initial years of follow-up[78]. Conversely, low levels of HDL-C and high TGs have been consistently associated with an increased risk of AF[79]. This indicates that further research is needed to understand the intricate dynamics between lipid metabolism and atrial arrhythmias.

Hypertension

The interplay between hypertension, AF, and MASLD reveals a complex relationship where each condition can worsen the other, establishing a vicious cycle that increases the risk of serious cardiovascular complications[80] (Figure 1D). MASLD is linked with various metabolic disturbances, including dyslipidemia and IR, which are often exacerbated by hypertension. IR is a defining characteristic of MASLD and can amplify the activity of the sympathetic nervous system, resulting in elevated blood pressure. In addition, IR may lead to the sodium and water renal retention, which intensifies hypertension by increasing blood volume. The persistent low-grade inflammation linked with MASLD can also influence the vascular system leading to vasoconstriction and further increase the blood pressure levels[81,82]. A cross sectional study in China demonstrated strong association of inflammatory indices, especially aggregate index of systemic inflammation with MASLD and opened the door for potential utility in risk stratification, thus reinforcing the role of chronic inflammation[83]. Recent findings suggest that MASLD not only increases the likelihood of developing hypertension but may also influence its onset at an early age, independent of other metabolic risk factors[24]. Furthermore, MASLD is associated with a gain-of-function variant in the angiotensin receptor type 1 gene in hypertensive individuals, specifically rs5186 A1166C. The findings indicate that MASLD may exacerbate the renin-angiotensin-aldosterone system (RAAS), resulting in elevated blood pressure through vasoconstriction and an increase in blood volume[84]. The positive correlation between elevated plasma aldosterone concentration (PAC) and the prevalence of MASLD in hypertensive patients supports this assertion[85]. Indeed, for every 5-unit increase in PAC, the risk of MASLD increased by a factor of 1.57[86]. Conversely, hypertension may contribute to the progression of MASLD, as evidenced by studies exhibiting an association of high blood pressure with liver scar tissue formation and worsening liver conditions, even when considering other factors like obesity and diabetes[87,88].

Hypertension is a well-recognized risk factor for AF, with evidence indicating that high blood pressure significantly contributes to the incidence of AF[89]. Individuals with hypertension face a 1.7-fold increased risk of developing AF compared to those with normal blood pressure, and hypertension is responsible for 1 in 6 AF cases[90]. High blood pressure significantly strains the heart, leading to LVH[9]. This leads to disruption of the heart's electrical pathways, promoting the development of AF. Moreover, high blood pressure also leads to the stiffening of arteries. The elevated pressure pulsatility and increased pulse wave velocity worsen LVH, impair diastolic function, and raise LV filling pressure, which eventually causes the left atrium to stretch[9]. This atrial remodeling constitutes a substrate for AF onset and persistence of AF. This progression is facilitated by the interplay of inflammation, oxidative stress and RAAS activation, in addition to the aging process[91]. The association of hypertension with AF is further highlighted by the CHADS2VASc score, a clinical tool used to assess stroke risk in AF patients. It incorporates hypertension as a critical factor, underscoring its relevance in the clinical context[92]. Therefore, addressing hypertension is essential not only for the prevention of AF and MASLD but also for improving overall cardiovascular health.

PROPOSED HYPOTHESIS

Inflammation and oxidative stress

Inflammation has emerged as a crucial link between AF and MASLD, two increasingly prevalent conditions[24]. Chronic inflammation associated with MASLD is driven by elevated levels of pro-inflammatory cytokines, including TNF-α and IL-6. These cytokines not only contribute to hepatic damage but also play a significant role in the pathogenesis of CVDs, such as AF[6]. A mice model reported early non-obese MASH resulting from IR and hepatic inflammation through TNFα as the key regulator[11]. TNF-α secretion facilitates the upregulation of various pro-inflammatory mediators through activation of nuclear factor kappa-B (NF-κB) signaling pathway resulting in hepatic inflammation and steatosis. On the other hand, IL-6 activates the JAK/STAT signaling pathway, leading to the transcriptional upregulation of acute-phase reactants, such as CRP and serum amyloid A. This process subsequently amplifies the hepatic inflammatory response and exerts systemic effects beyond the liver[93]. A cross-sectional study revealed elevated levels of high-sensitivity CRP, an inflammatory marker that is indicative of an increased risk of MASLD[94].

Numerous research studies have identified a link between circulating inflammatory markers, such as CRP and ILs, and the severity of AF, including its chronicity, type, and burden[95,96]. Over two decades ago, research suggested a link between AF and inflammation, particularly in the context of postoperative AF following cardiac surgery, which occurred with a high frequency (20%-50%). The incidence of postoperative AF typically peaks 2 to 3 days post-surgery, coinciding with the activation of systemic inflammatory pathways. This is evidenced by early elevations in plasma IL-1β, followed by increases in IL-6 and CRP, the latter being a sensitive yet nonspecific marker of systemic inflammation[97]. Increased concentrations of inflammatory cytokines, including IL-6 and TNF-α, have been recognized as critical contributors to atrial remodeling and electrical instability[34]. The activation of cardiac fibroblasts by inflammatory factors leads to a vicious cycle of inflammation and fibrosis, reinforcing the substrate for AF maintenance[98]. The activation of pathways such as NF-κB signaling has also been implicated in the regulation of ion channels and gap junction proteins, thereby enhancing the susceptibility to AF[99]. Therefore, atrial fibrosis, characterized by conduction disturbances, is exacerbated by inflammatory mediators and contributes to atrial remodeling-a process that perpetuates AF and increases the risk of thromboembolic events. While some studies demonstrate a clear association between elevated inflammatory markers and AF incidence, others suggest the need for a more nuanced understanding of how these markers interact with additional risk factors, such as obesity and dyslipidemia[100].

Inflammation may result in oxidative stress that surpasses the capacity of antioxidant defenses. Oxidative stress has been reported to play a crucial role in the pathogenesis of both MASLD and AF, is a critical factor in atrial remodeling, which in turn leads to cellular damage and inflammation within the atrial tissue[12]. Mitochondrial dysfunction is a key contributor to oxidative stress, affecting cellular homeostasis and promoting the initiation of AF via altered ion channel dynamics[101]. Studies have shown that ROS produced by mitochondria can activate Ca²⁺/calmodulin-dependent protein kinase II (CAMKII), which in turn phosphorylates the ryanodine receptor 2. This phosphorylation event is a precursor to the onset of AF, as evidenced by research conducted using mouse models. Furthermore, oxidative stress is known to intensify AF and encourages CAMKII to mediate the interaction between Ca²⁺ and calmodulin, thereby activating calmodulin[102].

The presence of excessive hepatic fat in MASLD leads to an elevation in ROS production, which in turn induces cellular damage and contributes to the development of inflammation and fibrosis[103]. In addition, the pathogenesis of MASLD in OSA largely centers around chronic intermittent hypoxia, which leads to the release of ROS and inflammatory mediators that contribute to hepatic inflammation and fibrosis[103]. One factor that mediates this effect is macrophage specific hypoxia inducing factor (HIF-1α), which is increased in OSA as well as MASLD through oxidative stress and mitochondrial injury[103,104]. HIF-1α influences the release of lysyl oxidase (LOX), which plays a role in cross-linking of extracellular matrix proteins and promotes fibrosis[105]. This hypothesis is supported by the finding that LOX levels are higher in patients with hepatic fibrosis[106]. HIF-2 is also implicated and results in dysregulated lipid metabolism which leads to severe hepatic steatosis[107]. Generally, prolyl hydroxylase domain (PHD) enzymes degrade HIFs. Hypoxia results in decreased PHD activity, enabling excessive HIF activity and consequent liver injury[108]. Furthermore, MASH and MASLD are linked to decreased production of adiponectin which exhibits anti-inflammatory properties in adipose tissue and may also be associated with AF, although reports on this association are conflicting[109]. Hypoadiponectinemia may partially elucidate the role of obesity and systemic inflammation in the association between MASLD and AF[110]. Therefore, chronic inflammation and oxidative stress associated with MASLD can exacerbate atrial structural changes, thus creating a vicious cycle that accelerates the onset of AF.

Gut microbiome

Alterations in gut microbiota composition can significantly impact both MASLD and AF through mechanisms involving inflammation and metabolic dysfunction[111]. The gut microbiota, which comprises a complex community of microorganisms, is essential in maintaining human health by influencing metabolism, immune function, and inflammation. Dysbiosis, defined as an imbalance in gut microbial populations has been reported in multiple diseases and shown to activate the immune system, eliciting chronic diseases[112-115]. The concept of gut-immune-heart axis and gut-immune-liver axis have been proposed to explain the impact of dysbiosis on AF and MASLD[116,117]. The "multiple hit model" of MASLD development identifies several contributing factors, including fat accumulation, IR, and genetic or environmental influences that disrupt gut integrity leading to dysbiosis[118]. Dysbiosis in turn can lead to increased intestinal permeability and the translocation of microbial products into the bloodstream, triggering systemic inflammatory responses and contribute to its pathogenesis by exacerbating liver inflammation and fibrosis[119]. In patients with AF, the recruitment of monocytes and macrophages to the atrial myocardium can lead to the release of pro-inflammatory cytokines, which may precipitate arrhythmias[120]. Moreover, the interaction between gut microbiota and the autonomic nervous system may also play a role in AF progression, indicating a regulatory effect of the gut-brain-heart axis that warrants further investigation through clinical and preclinical studies[116]. The progression of MASLD has been linked to metabolites produced by gut microbiota, such as short-chain fatty acids, bile acids, and trimethylamine-N-oxide. These metabolites can affect liver metabolism and inflammatory responses, highlighting the intricate relationship between gut microbial composition and liver health[117]. Additionally, these metabolites of intestinal flora equally participate in AF occurrence[120-122]. Therefore, further research is necessary to explore whether targeted interventions in gut microbiota could mitigate AF progression and improve patient outcomes.

Endothelial dysfunction

The endothelium, forming the inner surface of blood vessels, plays a vital role in maintaining vascular homeostasis by controlling blood flow, coagulation processes and vascular tone. Under normal physiological conditions, the endothelium generates mediators that promote vasodilation and inhibit both platelet aggregation and the proliferation of smooth muscle cells[10]. However, this balance is disrupted in MASLD, leading to impaired endothelial function and an increased risk of cardiovascular events[123]. Key components of this interplay include inflammation, oxidative stress, and dysregulation of vascular endothelial growth factor (VEGF) signaling. In patients with MASLD, Nitric oxide (NO) production, a vital mediator of endothelial health, is often compromised due to increased oxidative stress and inflammation. Elevated Asymmetric dimethylarginine levels, an endogenous inhibitor of endothelial NO synthase, are prevalent in MASLD[124]. The reduction in NO leads to diminished vasodilation, increased vasoconstriction leading to further suppression of NO synthesis, and consequently increased vascular resistance and blood pressure, thereby escalating cardiovascular risks including arrhythmias like AF[124].

The inflammatory response exacerbated by endothelial dysfunction involves the upregulation of adhesion molecules and the recruitment of inflammatory cells, which are further influenced by cytokines such as IL-1β and IL-18. These cytokines promote plaque formation and vascular stiffness which exacerbate atrial remodelling and thus, promote arrhythmogenesis[18]. Moreover, the inflammatory VEGF signaling pathway is integral to the pathophysiology of AF[125]. VEGF has been implicated in atrial remodeling, inflammation, and fibrosis, potentially leading to the initiation and maintenance of AF. By interacting with fibroblasts and modulating fibrotic pathways, VEGF may contribute to the structural changes in the atria that promote arrhythmia[125]. Emerging evidence suggests that endothelial dysfunction contributes to the maintenance of an arrhythmic substrate in patients with AF undergoing cardioversion and ablation who have a high risk of recurrence, further highlighting its importance in the pathogenesis[126] (Figure 1E).

Genetic factors

Genetic factors are increasingly acknowledged as significant in the pathogenesis of AF. The presence of a family history of AF in a first-degree relative independently elevates the risk of developing AF by twofold[127]. While monogenic inheritance has been described for a variety of genes, polygenic inheritance is more common[128,129]. Recent research has highlighted the significance of genetic predisposition in the pathogenesis of elevated AF risk among individuals with metabolic disorders, including MASLD. This understanding is rooted in the polygenic risk associated with specific genetic variants that demonstrate a correlation with both AF and MASLD[130]. Genome-wide association studies have pinpointed several SNPs that are linked to these conditions, indicating a common susceptibility that may be related to the dysregulation of lipid metabolism and inflammatory processes[131]. Among the significant genetic variants linked to MASLD are those located in the membrane-bound O-acyltransferase domain 7, PNPLA3, transmembrane 6 superfamily member 2 genes[132]. These variants are implicated in the development and progression of MASLD, which is closely linked to the risk of CVDs, including AF[133]. Additionally, Variants in genes associated with hypertension and lipid metabolism, such as the angiotensin receptor type 1 gene, have been linked to MASLD and its cardiovascular complications[24,133,134]. The cumulative risk of developing AF was particularly pronounced in individuals with high polygenic risk scores (PRS) and rare genetic variants linked to MASLD, with a significant hazard ratio for incident AF when compared to lower-risk groups. The incidence of AF reached as high as 28.55% by age 80 among high-risk individuals[17]. However, controversies surrounding the applicability of PRS and their clinical utility persist, necessitating further research to validate these findings and refine risk evaluation methodologies.

Renin angiotensin axis

Historically, research on the RAAS has primarily concentrated on its role in blood pressure regulation. However, more recently, significant attention has been directed towards understanding RAAS's influence on a wider array of diseases, particularly through its impact on local tissue dynamics[24]. RAAS can be divided into the traditional RAAS pathway (or classic RAAS) mediated by angiotensin II (AII), and the non-classic RAAS pathway mediated by angiotensin 1-7. Both pathways function within the heart and lungs. In the cardiac context, the classical RAAS predominates over the non-classical RAAS, significantly impacting hemodynamic processes and tissue remodeling. This predominance is linked to dysfunctions in cardiomyocytes and endothelial cells, thereby increasing the risk of AF[135,136]. AII, a key component of RAAS and a pro-inflammatory mediator, has the capacity to upregulate cytokines, stimulate cell proliferation, and modulate extracellular matrix metabolism through the AII type 1 receptor. The AII type 1 receptor is notably distributed across a range of organs, including blood vessels, the heart, the liver, the brain, the lungs, the kidneys, and the adrenal cortex. This widespread distribution suggests its potential involvement in the pathogenesis of both MASLD and AF[137]. AII causes vasoconstriction, stimulates aldosterone release, and promotes inflammation and fibrosis within the cardiac tissue[138]. This inturn leads to increased atrial pressure, fibrosis and electrical remodelling; all of which exacerbate the risk of AF[139].

Recent findings indicate that MASLD may exacerbate RAAS activity, resulting in increased vasoconstriction and elevated blood volume, which collectively elevate blood pressure[139]. Furthermore, RAAS plays a pivotal role as a lipid metabolism signaling pathway in the hepatic tissue of individuals with MASLD. In rodent studies, the suppression of RAAS has been found to reduce obesity caused by high-fat diets[140]. Moreover, rodent models with knockouts of RAAS-related genes, such as renin and angiotensin-converting enzyme, or those with a liver-specific deletion of the AT1 receptor, have shown improvements in hepatic steatosis[141]. RAAS activation downregulates the expression of genes associated with fatty acid oxidation, thereby suppressing the oxidative metabolism of fatty acids. Additionally, specific cytokines (TNF-α, MCP-1, and IL-6) and IR contribute to RAAS-mediated exacerbation of MASLD[110]. RAAS meditates the secretion of aldosterone that is essential in regulating the body’s water and electrolyte balance[142]. Recent studies have linked elevated PAC to the development of MASLD[85,86]. In addition to chronic inflammation, oxidative stress, and IR, aldosterone contributes to the reduction of both circulating adiponectin and its expression in visceral adipose tissue. Moreover, this process initiates a direct sequence of events culminating in the activation of hepatic stellate cells, which in turn leads to liver fibrosis, primarily through NLRP3 inflammasome activation[143,144]. Given the interconnectedness of these conditions, understanding the role of RAAS becomes critical in addressing the pathogenesis of AF in patients with MASLD (Figure 2).

Figure 2 Association between metabolic dysfunction-associated steatotic liver disease and atrial fibrillation. AFib: Atrial fibrillation; FA: Fatty acid; CPAP: Continuous positive airway pressure; GLP-1RA; Glucagon like peptide-1 receptor agonist; iCa: Intracellular calcium; MASLD: Metabolic dysfunction-associated steatotic liver disease; OSA: Obstructive sleep apnea; RAAS: Renin-angiotensin-aldosterone-system; TNF-α: Tumor necrosis factor-alpha; VEGF: Vascular endothelial growth factor. Created in BioRender (Supplementary material).

CLINICAL IMPLICATIONS

The clinical implications of MASLD extend beyond hepatic health, emphasizing the importance of a holistic understanding of its cardiovascular consequences[145]. This patient population is increasingly vulnerable to arrhythmias, necessitating comprehensive cardiovascular risk assessment and management strategies tailored to mitigate these risks[146]. Studies reported MASLD as an independent risk factor for recurrent arrhythmia following ablation after adjusting for body mass index and glycemic control[147,148]. This finding underscores the importance of integrating MASLD management into broader treatment strategies for cardiac arrhythmia prevention and management. In recognition of this, both the American Association for the Study of Liver Diseases and the European Association for the Study of the Liver advocate for the regular evaluation of cardiovascular risk factors in patients with MASLD. Physicians should, therefore, be vigilant about the potential cardiovascular implications of MASLD, including its association with arrhythmias such as AF.

Management of MASLD primarily revolves around lifestyle modifications and pharmacological interventions. Adopting lifestyle changes, such as altering one's diet, engaging in more physical exercise, managing body weight, and quitting smoking, is crucial for enhancing patient outcomes and controlling risk factors linked to both MASLD and AF[149]. Dietary management is one of the most significant nonpharmacologic strategies for MASLD. A balanced, nutrient-rich diet can influence mechanisms related to AF pathogenesis, including inflammation and oxidative stress[145]. The Mediterranean diet and the Dietary Approaches to Stop Hypertension diet have garnered significant attention for their efficacy in managing MASLD and enhancing cardiovascular health, while concurrently reducing hepatic fat accumulation[149]. Increasing physical activity is another critical intervention for patients with MASLD. Regular exercise has been shown to improve metabolic health, facilitate weight loss, and enhance overall cardiovascular fitness, which are vital for reducing AF risk[149]. Weight reduction is essential as it can result in improvements in liver health and reduction in AF risk factors[145]. This is further supported by reduction in arrhythmia recurrence noted in post-ablation patients with risk factor modification acknowledged as a crucial factor[56,150]. Finally, collaborative efforts implemented by a multidisciplinary care team, including dietitians, nurses, and pharmacists, could be vital for delivering comprehensive nutritional interventions and lifestyle modifications tailored to each patient's unique needs thereby enhancing adherence to the recommended lifestyle changes and improving clinical outcomes.

While diet and lifestyle interventions serve as the cornerstone of treatment, they are often insufficient or unsustainable for many patients[50]. Specific interventions targeting MASLD as part of arrhythmia management remain understudied. However, the relationship between AF and MASLD persists across various histological categories of MASLD, including simple steatosis and cirrhosis, indicating that the severity of liver fibrosis may be a crucial predictor for the development of AF[18]. Therefore, as the disease progresses, particularly in cases with significant fibrosis, patients may require pharmacological therapies aimed at reducing hepatic inflammation, fibrosis, and steatohepatitis. Resmetirom has emerged as the first Food and Drug Administration-approved drug for effective management of MASLD, functioning as a thyroid hormone receptor β (THR-β) agonist. This medicine helps by turning on the THR receptor in liver cells. This reduces the creation of new fats, increases the breakdown of fatty acids, and offers benefits against inflammation and scarring[151]. The direct impact of Resmeritom on the incidence of AF remains unstudied. The study noted that Resmetirom had no effect on heart rate and was not linked to arrhythmias, suggesting a favorable cardiovascular safety profile in this patient population, however, more research is required to establish risk reduction of AF in patients with MASLD[151].

Other potential pharmacological treatments include Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and thiazolidinediones (TZD). Multiple phase II and phase III trials have highlighted the efficacy of GLP-1RAs in reducing hepatic fat content and liver histological inflammation and fibrosis among MASLD patients[152-154]. These medications have been incorporated in the guidelines to manage diabetes, a major metabolic risk factor for arrhythmia[155,156]. Furthermore, obesity plays a notable role in the prognosis of AF among MASLD patients and is an independent risk factor for AF[56]. Thus, the weight loss effects linked to GLP-1RAs, especially when used in conjunction with glucose-dependent insulinotropic peptide or glucagon, could potentially lower the risk of AF in individuals with MASLD[157]. GLP-1RAs have been studied for their impact on AF in patients with T2DM and may have a beneficial effect on reducing the incidence of AF. A real-world cohort study found that GLP-1RA use was associated with a lower risk of AF compared to dipeptidyl peptidase-4 inhibitors but showed no significant difference when compared to sodium-glucose cotransporter 2 inhibitors[158]. Meta analysis of randomized clinical trials have provided mixed results however, one meta-analysis reported no significant increase in the risk of AF with GLP-1RA use while another meta-analysis specifically focusing on semaglutide found a significant reduction in the incidence of AF by 42% compared to placebo[159,160]. In the context of TZDs, Pioglitazone has been shown to decrease liver fat and/or improve liver histological features in patients with MASLD, in addition to raising the levels of circulating adiponectin[161-163]. The American Association of Clinical Endocrinologists and the American Association for the Study of Liver Diseases also recommend pioglitazone for patients with T2DM and biopsy-proven MASH, a condition closely related to MASLD, due to its efficacy in improving liver histology and cardiometabolic outcomes[164]. A meta-analysis examining the use of pioglitazone and its association with AF risk indicates that pioglitazone may offer protective effects against AF in patients with diabetes[165]. While specific data on the impact of pioglitazone on the risk of AF in patients with MASLD is limited, its overall cardiovascular benefits, including the reduction of AF incidence in broader populations, suggest a potential positive impact in this subgroup as well.

Management of underlying risk factors could have a role in mitigating the risk of AF in MASLD. The relationship between MASLD and hypertension is characterized by a reciprocal reinforcement, where each condition exacerbates the other. In the context of AF pathophysiology, a reduction in blood pressure diminishes the load on the LV. Therefore, implementing more stringent blood pressure control could be advantageous in reducing LVH, myocardial fibrosis, diastolic dysfunction, and the retrograde stretching and structural remodeling of the atria. Recent research has indicated the potential role of RAAS blockers, including angiotensin receptor blockers and ACE inhibitors, in treating cardiovascular complications associated with MASLD. These agents can reduce hepatic inflammation and fibrosis, which are key components of MASLD, and also mitigate atrial structural remodeling and fibrosis, which are critical in the pathogenesis of AF[166,167]. The American College of Cardiology/American Heart Association guidelines suggest that RAAS blockers may have a role in preventing AF, particularly in patients with heart failure or hypertension, although the evidence is not robust enough to make a strong recommendation for their use solely for AF prevention[168]. In summary, RAAS blockade may reduce the risk of AF in patients with MASLD by addressing common pathophysiological pathways such as inflammation and fibrosis. However, while promising, the evidence is not yet conclusive, and further large-scale, long-term studies are needed to establish definitive clinical guidelines.

Statins, known for their cholesterol-lowering properties, are predominantly utilized in the treatment of atherosclerosis. Recently, there has been a growing interest in exploring their potential therapeutic role in managing MASLD[169,170]. A retrospective cohort study identified a protective association with the progression of fibrosis risk in primary care patients with MASLD who were prescribed moderate and high-intensity statins[169]. Statins have been shown to improve liver biochemistries and reduce cardiovascular events in patients with MASLD[171]. ACC and AHA recommend the use of statins in patients with chronic liver disease, including MASLD, when indicated for cardiovascular risk management[172]. Statins have been investigated for their potential role in the management of AF due to their pleiotropic effects, including anti-inflammatory and antioxidant properties. However, the evidence regarding their efficacy in preventing AF is mixed. In a study involving elderly patients diagnosed with AF, the American Heart Association identified that statin therapy is independently linked to a 13% to 17% reduction in stroke risk. This evidence indicates that statins may serve as an undervalued strategy for mitigating stroke risk in the AF population[173]. While retrospective data looks promising, a larger placebo-controlled trial of rosuvastatin did not demonstrate a reduction in postoperative AF[174]. The European Heart Rhythm Association, the European Association of Cardiovascular Prevention and Rehabilitation and Heart Rhythm Society have noted that while low HDL-C and high TG levels are associated with increased AF risk, the evidence for targeting LDL-C or TC to reduce AF risk is weak[90]. Therefore, while statins are beneficial for cardiovascular risk reduction in patients with MASLD, their role in specifically reducing the risk of AF in this population is not well-established. OSA is another risk factor implicated in shared pathogenesis of AF and MASLD. Research indicates that the implementation of continuous positive airway pressure (CPAP) therapy in individuals with OSA can markedly decrease the recurrence of AF. A meta-analysis involving 1087 patients demonstrated that CPAP therapy was associated with a marked decrease in AF recurrence rates following treatment for the arrhythmia, such as catheter ablation, thereby highlighting management of OSA for long-term treatment of AF[60].

An important aspect of management and mitigation of risk is screening. Liver stiffness measurement by transient elastography and FIB-4 score are recommended screening protocols for MASLD patients, as endorsed by the American Gastroenterological Association and the American Diabetes Association[175,176]. Regarding electrocardiogram screening for patients with MASLD, additional research is necessary before making recommendations. The USPSTF, in a 2022 update to their 2018 guidelines, determined that there is currently insufficient evidence to evaluate the advantages and disadvantages of screening for AF[177].

Future research should explore the impact of emerging MASLD therapeutic agents on the incidence and recurrence of cardiac arrhythmias. For example, gut microbiome and dysbiosis have garnered interest in the pathogenesis of AF and MASLD. Exploratory treatments for MASLD, such as dietary changes, prebiotics, probiotics, and fecal microbiota transplantation, are being investigated with the goal of reestablishing a balanced microbiota. This approach is intended to enhance liver function and alleviate metabolic dysfunction[118]. However, further investigations are warranted to fully understand the causal relationships and underlying mechanisms involved, as well as to identify specific microbial targets for clinical intervention. Understanding the role of these treatments in modifying arrhythmogenic risk may provide a new avenue for comprehensive management strategies targeting both MASLD and associated cardiovascular complications.

CONCLUSION

MASLD is increasingly recognized as a significant risk factor for various cardiovascular conditions, particularly AF. This association is independent of other common risk factors like age, sex, and diabetes (Figure 3). The severity of MASLD does not seem to directly influence the risk of AF, suggesting that even early stages of liver disease can increase susceptibility to this arrhythmia. Given the rising prevalence of both MASLD and AF, especially among aging populations, the clinical implications are profound, necessitating enhanced cardiovascular risk assessments and targeted management strategies for at-risk individuals. As the healthcare burden associated with AF continues to grow, understanding the interplay between MASLD and AF becomes crucial for public health initiatives and clinical practice. Strategies that integrate the management of both conditions may improve patient outcomes and reduce healthcare costs associated with cardiovascular events and complications related to liver disease.

Figure 3 Central illustration. AFib: Atrial fibrillation; FA: Fatty acid; CPAP: Continuous positive airway pressure; GLP-1RA; Glucagon like peptide-1 receptor agonist; iCa: Intracellular calcium; MASLD: Metabolic dysfunction-associated steatotic liver disease; OSA: Obstructive sleep apnea; RAAS: Renin-angiotensin-aldosterone-system; TNF-α: Tumor necrosis factor-alpha; VEGF: Vascular endothelial growth factor. Created in BioRender (Supplementary material).